Angioinvasive Trichophyton rubrum associated necrotizing fasciitis in an immunocompromised patient

Key clinical message Angioinvasive dermatophytosis with necrotizing fasciitis can be a rare complication in immunocompromised patients with early surgical debridement, 12 weeks of oral terbinafine, and reduction in immunosuppression being a viable management strategy.

market to treat patients with autoimmune conditions, malignancies, and solid organ transplants, there is an increasing population of immunosuppressed patients who may be at risk for invasive dermatophyte infections.This case presents a patient with recurrent tinea corporis who developed angioinvasive dermatophytosis in the setting of ongoing immunosuppressive treatment for chronic lymphocytic leukemia (CLL) and immune thrombocytopenia purpura (ITP).

| CASE PRESENTATION
A 69-year-old male with a history CLL, ITP, and recurrent tinea corporis presented to the with an ulcerating lesion at the site of a previously diagnosed tinea corporis infection of his right medial ankle.
One month prior to presentation, the patient was started on high-dose steroids for treatment of refractory ITP.After 2-3 weeks of experiencing a limited response to steroid treatment, he was started on rituximab and ultimately hospitalized for refractory ITP.During this hospitalization, the patient's ITP was thought to be triggered by CLL prompting the initiation of ibrutinib for treatment.Following the initiation of ibrutinib, a new pruritic, painful skin lesion on his right medial ankle developed which was evaluated by dermatology.This skin lesion was painful to the touch and noted to be a well-demarcated bright red plaque with scattered hemorrhagic, dusky, purple papules within the plaque.There was a collarette of scale overlying the edge of the lesion.A skin scraping with potassium hydroxide preparation demonstrated numerous branching hyphae.A biopsy of the lesion was deferred due to thrombocytopenia (11,000/cmm).Topical terbinafine 1% cream twice daily was started for presumed superficial tinea corporis infection.The patient was subsequently discharged once his thrombocytopenia stabilized.Less than 1 week from discharge, the patient's distal right lower extremity became progressively more edematous with new ulceration and serosanguinous drainage (Figure 1).He presented to the hospital again and was admitted for a second time (Table 1).Further evaluation with a computed tomography scan of the right lower extremity demonstrated diffuse subcutaneous edema with pooling of fluid along the superficial fascia.There were no signs of focal fluid collection or subcutaneous emphysema.Due to clinical concern for necrotizing fasciitis, the patient was urgently taken to the operating room by general surgery where he underwent four-compartment fasciotomy of the right lower extremity as well as excisional debridement of the involved area at the right ankle until healthy appearing and bleeding tissue was reached.
Intraoperatively, there was extensive necrosis involving the dermis, subcutaneous adipose tissue, and superficial fascial layers which were debrided.The underlying At the fasciotomy sites in the leg, there was a positive finger sign between the adipose and the fascia as well as between the fascia and the muscle, without frankly necrotic tissue in this part of the leg.While the fascia and muscle appeared healthy, this clinical finding of easy separation between the two tissue planes was thought to be representative of early-stage infection in which necrosis of the epimysium occurred without progression to widespread tissue necrosis.Therefore, no further sharp debridement was performed.Pulse lavage irrigation and debridement with nine liters of normal saline was then performed at the surgical sites.
Operating room cultures grew Trichophyton rubrum, as well as methicillin-susceptible Staphylococcus aureus and Enterococcus faecalis.Pathology exam demonstrated numerous branching, septated fungal hyphae within purulent inflammation in subcutaneous tissue, fascia, and also intravascularly within a thrombosed blood vessel (Figure 2).On postoperative day three, the patient developed elevated temperatures and was noted to have skin findings on his left lower extremity similar to the early stages of his right lower extremity infection.On postoperative day four, he underwent excisional debridement of his new left lower extremity lesion at bedside.Deep tissue specimens of his left lower extremity lesion grew T. rubrum and pathological exam demonstrated purulent inflammation with necrosis and branching septated fungal hyphae.On postoperative day six, his right lower extremity wounds showed stability (Figure 3).
Ultimately, this patient received daily wound care with multiple dressing changes which allowed for his surgical wounds to granulate and fill in appropriately.He was treated with a three-week course of antibacterials for methicillin susceptible S. aureus and E. faecalis cultured from the right lower extremity, and oral terbinafine 250 mg daily for 12 weeks for his invasive dermatophyte infection of both extremities.Given the extensive debridement, his right lower extremity wounds were covered with split thickness skin grafts 6 weeks postoperatively.At a clinic visit 2 weeks after completing terbinafine treatment, the patient had well healed skin grafts with no signs of recurrent infection.

| DISCUSSION
Given the keratinophilic nature of dermatophytes, invasion deeper than the stratum corneum in the skin is rare. 1 However, this case demonstrates that increased immunosuppression in patients with superficial dermatophyte infections may predispose to angioinvasive disease involving deeper tissues.The most common predisposing factors associated with invasive dermatophyte infections include: superficial dermatophytosis, solid organ transplant, topical immunosuppressants, gene mutations, diabetes, and trauma. 6The development of our patient's angioinvasive dermatophyte infection was preceded by increasing immunosuppression with high dose steroids, rituximab, and ibrutinib in the setting of worsening CLL and ITP.][9][10] Classically, these fungal infections include invasive yeast infections such as candidiasis, mold infections including aspergillosis and fusariosis, endemic fungal disease, and classic opportunistic infections such as cryptococcus and pneumocystis jiroveci. 8Invasive dermatophyte infections are rarely considered when increasing a patient's immunosuppression.In the setting of superficial dermatophyte infections, clinicians should be aware of the possibility of invasive disease when increasing immunosuppression similar to the more classic non-dermatophyte invasive fungal infections.When a superficial dermatophyte infection presents with a dusky appearance and/or leads to pain out of proportion to exam, there should be concern for invasive disease, including necrotizing fasciitis, and early biopsy/surgical intervention should be considered.Antifungal treatment guidance for invasive dermatophyte infections is scarce.When dermatophyte infections extend beyond the stratum corneum, it is generally recommended to transition from topical to oral therapy.There is not a consensus on the preferred oral antifungal.A recent systematic review of invasive dermatophyte infections showed that the most commonly used agents were terbinafine and itraconazole. 6However, a number of patients were treated with other antifungals including griseofulvin, fluconazole, amphotericin B, and posaconazole. 6here was additional variability in the duration of treatment for the cases reviewed.We treated our patient with oral terbinafine 250 mg daily for 12 weeks.This drug, dose, and duration of therapy in combination with surgical debridement and reduced immunosuppression resulted in clinical clearance of infection.

| CONCLUSIONS
This case demonstrates a rare presentation of an angioinvasive dermatophyte necrotizing soft tissue infection in the setting of hematologic malignancy and increasing immunosuppression.In patients with superficial dermatophyte infections, immunosuppression may predispose to deeper infection and potentially angioinvasive disease.If superficial dermatophyte lesions appear dusky with pain out of proportion to exam, early biopsy should be pursued to assess for deeper invasion.Early and aggressive surgical debridement with assessment and washout of the fascial compartments can halt progression of necrotizing soft tissue infections and result in limb salvage.This case additionally adds to the paucity of literature on management strategies of angioinvasive dermatophyte infections which included surgical debridement, reduction of immunosuppression, and a 12-week course of oral terbinafine 250 mg daily.

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I G U R E 1 Well-demarcated annular plaque of the medial right lower extremity with dusky hemorrhagic crusts.T A B L E 1 Events preceding hospital admission for dermatophyte associated necrotizing fasciitis.• Right lower extremity lesion noted • Prednisone dose change from 50 mg BID to 80 mg daily 30 • Dermatology consulted • KOH of skin scraping with branching fungal hyphae • Topical terbinafine 1% cream BID application 31 • Discharge from hospital 32 • Prednisone dose change from 80 mg daily to 60 mg daily 36 • Hospital admission for necrotizing fasciitis of right lower extremity muscle layers, tendons, and deep fascia appeared alive and healthy.Tissue was sent for culture and pathology.